# ACKR1

## Overview
The ACKR1 gene encodes the atypical chemokine receptor 1, also known as the Duffy antigen receptor for chemokines (DARC), which is a transmembrane glycoprotein primarily expressed on red blood cells and endothelial cells. Unlike typical G protein-coupled receptors (GPCRs), ACKR1 does not signal through G proteins but instead functions as a chemokine scavenger, modulating chemokine availability and activity in the bloodstream and tissues (Nibbs2013Immune; Gutjahr2021The). This receptor plays a critical role in immune regulation by binding and sequestering inflammatory chemokines, thereby influencing leukocyte migration and immune responses (Bonecchi2016Atypical). The gene's expression and function have significant clinical implications, particularly in relation to infectious diseases such as malaria, where the Duffy-null phenotype confers resistance to Plasmodium vivax (Rappoport2018The). Additionally, ACKR1 is involved in various pathological conditions, including cancer and inflammatory diseases, highlighting its importance in both health and disease (Jenkins2019Atypical).

## Structure
The ACKR1 protein, also known as the Duffy antigen receptor for chemokines (DARC), is a glycoprotein expressed on red blood cells and endothelial cells. It is a seven-transmembrane G protein-coupled receptor (GPCR) that binds chemokines, although it lacks typical GPCR signaling due to its atypical nature (Gutjahr2021The). The protein's structure includes an extracellular N-terminus, which is flexible and contains multiple epitopes crucial for binding chemokines like CXCL12 in its dimeric form (Gutjahr2021The). This N-terminal region is also subject to glycosylation, which may influence its interactions with chemokines (Davis2015Distinct).

The ACKR1 gene produces two distinct transcript isoforms, DARC1/Isoform A and DARC2/Isoform B, which differ in their N-terminal amino acids and result in protein products of 338 and 336 amino acids, respectively (Davis2015Distinct). These isoforms have unique glycosylation and enzymatic cleavage sites, potentially leading to functional divergence (Davis2015Distinct). The protein's N-terminus is involved in binding interactions with chemokines, and its structure has been studied using techniques like NMR spectroscopy and isothermal titration calorimetry (Gutjahr2021The). The ACKR1 protein acts as a chemokine sink and reservoir, influencing chemokine availability and function (Gutjahr2021The).

## Function
ACKR1, also known as atypical chemokine receptor 1, plays a crucial role in regulating chemokine activity and immune cell migration in healthy human cells. It is primarily expressed on mature erythrocytes and endothelial cells of post-capillary venules. ACKR1 functions as a chemokine buffer by binding inflammatory chemokines, which helps maintain proper leukocyte recruitment during inflammation and prevents desensitization of conventional chemokine receptors on leukocytes (Nibbs2013Immune; Bonecchi2016Atypical). 

ACKR1 is involved in chemokine transcytosis through endothelial cells, transporting chemokines from the basolateral to the luminal side, and retaining them on the apical surface to promote signaling through GPCRs. This process is essential for directing immune responses, such as neutrophil diapedesis, by concentrating chemokines at endothelial junctions to guide neutrophils and prevent reverse migration (Crawford2023Prospects). 

In erythrocytes, ACKR1 acts as a chemokine sink, capturing chemokines at times of high serum levels and releasing them when abundance is low, thus modulating chemokine availability and leukocyte migration (Nibbs2013Immune). This function is particularly relevant in individuals with the Duffy-null phenotype, who lack ACKR1 expression on erythrocytes, leading to higher circulating chemokine levels (Bonecchi2016Atypical).

## Clinical Significance
Mutations and alterations in the ACKR1 gene, also known as the Duffy antigen receptor for chemokines (DARC), have significant clinical implications. The Duffy-null phenotype, resulting from a specific single nucleotide polymorphism (SNP) rs2814778, is prevalent in individuals of African descent. This mutation disrupts the GATA1 transcription factor binding site, leading to a lack of ACKR1 expression on erythrocytes. This phenotype confers resistance to Plasmodium vivax malaria but is associated with benign ethnic neutropenia, characterized by low neutrophil counts (Rappoport2018The).

Altered expression of ACKR1 is linked to various infectious and inflammatory diseases. In malaria, ACKR1 serves as a target for the Duffy Binding Protein, and blocking this interaction can prevent infection by non-falciparum types like P. vivax (Crawford2023Prospects). In HIV, the role of ACKR1 is less clear, but it may facilitate infection or maintain a viral reservoir (Crawford2023Prospects). The gene is also implicated in asthma, where decreased erythrocyte ACKR1 expression correlates with increased IgE levels and asthma susceptibility (Crawford2023Prospects).

In cancer, particularly breast cancer, ACKR1 expression influences tumor immune response and survival outcomes. High levels of ACKR1 in tumors are associated with longer relapse-free survival, while its expression correlates with proinflammatory chemokines like CCL2 and CXCL8 (Jenkins2019Atypical).

## Interactions
ACKR1, also known as the Duffy antigen receptor for chemokines (DARC), participates in various interactions with proteins and chemokines. It binds with high affinity to the dimeric form of the chemokine CXCL12, facilitated by its flexible N-terminal domain. This interaction is significant in regulating the monomer-dimer equilibrium of CXCL12, which may influence hematopoiesis in the bone marrow (Gutjahr2021The). ACKR1 also interacts with the Duffy Binding Protein (DBP) secreted by Plasmodium vivax and P. knowlesi, which is crucial for the parasite's entry into red blood cells. This interaction can be inhibited by blocking the DBP-ACKR1 binding interface with chemokines or antibodies (Crawford2023Prospects).

In the context of infectious diseases, ACKR1 is targeted by Staphylococcus aureus toxins such as LukED and HlgAB, which bind to its N-terminus, potentially altering receptor conformation and causing hemolysis and vascular leakage (Crawford2023Prospects). ACKR1 also plays a role in chemokine regulation during inflammation by binding chemokines at inflamed sites, which can influence immune responses and inflammation (Crawford2023Prospects). These interactions highlight ACKR1's role in modulating chemokine availability and its involvement in various physiological and pathological processes.


## References


[1. (Davis2015Distinct) Melissa B. Davis, Andrea Walens, Rupali Hire, Kauthar Mumin, Andrea M. Brown, DeJuana Ford, Elizabeth W. Howerth, and Michele Monteil. Distinct transcript isoforms of the atypical chemokine receptor 1 (ackr1) / duffy antigen receptor for chemokines (darc) gene are expressed in lymphoblasts and altered isoform levels are associated with genetic ancestry and the duffy-null allele. PLOS ONE, 10(10):e0140098, October 2015. URL: http://dx.doi.org/10.1371/journal.pone.0140098, doi:10.1371/journal.pone.0140098. This article has 16 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0140098)

[2. (Jenkins2019Atypical) Brittany D. Jenkins, Rachel N. Martini, Rupali Hire, Andrea Brown, Briana Bennett, I’nasia Brown, Elizabeth W. Howerth, Mary Egan, Jamie Hodgson, Clayton Yates, Rick Kittles, Dhananjay Chitale, Haythem Ali, David Nathanson, Petros Nikolinakos, Lisa Newman, Michele Monteil, and Melissa B. Davis. Atypical chemokine receptor 1 (darc/ackr1) in breast tumors is associated with survival, circulating chemokines, tumor-infiltrating immune cells, and african ancestry. Cancer Epidemiology, Biomarkers &amp; Prevention, 28(4):690–700, April 2019. URL: http://dx.doi.org/10.1158/1055-9965.epi-18-0955, doi:10.1158/1055-9965.epi-18-0955. This article has 44 citations.](https://doi.org/10.1158/1055-9965.epi-18-0955)

[3. (Rappoport2018The) Naama Rappoport, Amos J. Simon, Ninette Amariglio, and Gideon Rechavi. The duffy antigen receptor for chemokines, <scp>ackr</scp>1,– ‘jeanne <scp>darc</scp>’ of benign neutropenia. British Journal of Haematology, 184(4):497–507, December 2018. URL: http://dx.doi.org/10.1111/bjh.15730, doi:10.1111/bjh.15730. This article has 29 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1111/bjh.15730)

[4. (Nibbs2013Immune) Robert J. B. Nibbs and Gerard J. Graham. Immune regulation by atypical chemokine receptors. Nature Reviews Immunology, 13(11):815–829, October 2013. URL: http://dx.doi.org/10.1038/nri3544, doi:10.1038/nri3544. This article has 320 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/nri3544)

[5. (Bonecchi2016Atypical) Raffaella Bonecchi and Gerard J. Graham. Atypical chemokine receptors and their roles in the resolution of the inflammatory response. Frontiers in Immunology, June 2016. URL: http://dx.doi.org/10.3389/fimmu.2016.00224, doi:10.3389/fimmu.2016.00224. This article has 188 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fimmu.2016.00224)

[6. (Crawford2023Prospects) Kyler S. Crawford and Brian F. Volkman. Prospects for targeting ackr1 in cancer and other diseases. Frontiers in Immunology, March 2023. URL: http://dx.doi.org/10.3389/fimmu.2023.1111960, doi:10.3389/fimmu.2023.1111960. This article has 9 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fimmu.2023.1111960)

[7. (Gutjahr2021The) Julia C. Gutjahr, Kyler S. Crawford, Davin R. Jensen, Prachi Naik, Francis C. Peterson, Guerric P. B. Samson, Daniel F. Legler, Johan Duchene, Christopher T. Veldkamp, Antal Rot, and Brian F. Volkman. The dimeric form of cxcl12 binds to atypical chemokine receptor 1. Science Signaling, August 2021. URL: http://dx.doi.org/10.1126/scisignal.abc9012, doi:10.1126/scisignal.abc9012. This article has 23 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1126/scisignal.abc9012)